Mouse model of human RPE65 P25L hypomorph resembles wild type under normal light rearing but is fully resistant to acute light damage.

Human RPE65 mutations cause a spectrum of blinding retinal dystrophies from severe early-onset disease to milder manifestations. The RPE65 P25L missense mutation, though having <10% of wild-type (WT) activity, causes relatively mild retinal degeneration. To better understand these mild forms of RPE65-related retinal degeneration, and their effect on cone photoreceptor survival, we generated an Rpe65/P25L knock-in (KI/KI) mouse model. We found that, when subject to the low-light regime (∼100 lux) of regular mouse housing, homozygous Rpe65/P25L KI/KI mice are morphologically and functionally very similar to WT siblings. While mutant protein expression is decreased by over 80%, KI/KI mice retinae retain comparable 11-cis-retinal levels with WT. Consistently, the scotopic and photopic electroretinographic (ERG) responses to single-flash stimuli also show no difference between KI/KI and WT mice. However, the recovery of a-wave response following moderate visual pigment bleach is delayed in KI/KI mice. Importantly, KI/KI mice show significantly increased resistance to high-intensity (20 000 lux for 30 min) light-induced retinal damage (LIRD) as compared with WT, indicating impaired rhodopsin regeneration in KI/KI. Taken together, the Rpe65/P25L mutant produces sufficient chromophore under normal conditions to keep opsins replete and thus manifests a minimal phenotype. Only when exposed to intensive light is this hypomorphic mutation manifested physiologically, as its reduced expression and catalytic activity protects against the successive cycles of opsin regeneration underlying LIRD. These data also help define minimal requirements of chromophore for photoreceptor survival in vivo and may be useful in assessing a beneficial therapeutic dose for RPE65 gene therapy in humans.

A Southwestern Tribal Perspective on Traditional and Commercial Tobacco.

American Indian or Alaska Natives have the highest rates of current cigarette (36.5%) and smokeless tobacco use (5.3%), and tobacco product (40.1%) and the second highest rate of current cigar use (6.1%) compared to all other racial-ethnic groups in the U.S. rates of American Indian or Alaska Native tobacco use vary by gender. Few studies examine perceptions of tobacco use among tribal members residing on and off the reservation. This study fills a gap in the literature by reporting the perceptions of 34 enrolled members of a southwestern tribe who reside on and off a tribal land using a Community-Based Participatory Research (CBPR) design through a collaboration between a university and a tribal health program. Researchers conducted seven focus groups; four on the southwest reservation and three within an urban community. The discussions were audio-recorded, transcribed, and analyzed using a multi-investigator consensus model. The use of tobacco (commercial or traditional) in southwest tribes is essential to cultural practices. Results depicted different views on cultural meaning and health impacts of commercial and traditional tobacco. Findings suggest the importance of local research to understand dimensions of tobacco use before moving forward with tobacco cessation programming.